Designing Synthetic Polymers for Nucleic Acid Complexation and Delivery: From Polyplexes to Micelleplexes to Triggered Degradation

Abstract

Gene delivery as a therapeutic tool continues to advance toward impacting human health, with several gene therapy products receiving FDA approval over the past 5 years. Despite this important progress, the safety and efficacy of gene therapy methodology requires further improvement to ensure that nucleic acid therapeutics reach the desired targets while minimizing adverse effects. Synthetic polymers offer several enticing features as nucleic acid delivery vectors due to their versatile functionalities and architectures and the ability of synthetic chemists to rapidly build large libraries of polymeric candidates equipped for DNA/RNA complexation and transport. Current synthetic designs are pursuing challenging objectives that seek to improve transfection efficiency and, at the same time, mitigate cytotoxicity. This Perspective will describe recent work in polymer-based gene complexation and delivery vectors in which cationic polyelectrolytes are modified synthetically by introduction of additional components�including hydrophobic, hydrophilic, and fluorinated units�as well as embedding of degradable linkages within the macromolecular structure. As will be seen, recent advances employing these emerging design strategies are promising with respect to their excellent biocompatibility and transfection capability, suggesting continued promise of synthetic polymer gene delivery vectors going forward.

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development

“…Cationic polymers take advantage of the distinct pH environment of endosomes to initiate the endosome escape and nucleotide release . However, the excess charge on the cationic polymers (i.e., poly­(ethylenimine), poly- l -lysine, polyamidoamine) has resulted in cytotoxicity and insufficient therapeutic effects. − Nevertheless, researchers have investigated the utilization of cationic polymers through their conjugation with hydrophilic blocks or the incorporation of degradable and reducible linkers, with the aim of mitigating their cytotoxic effects. ,,− …”

“…However, there are drawbacks to using such carriers, including toxicity, inflammatory response, and reduced nucleotide release because of their high charge. High positive charge on the polymers can be modulated by adding functional groups (i.e., esters), which moderate the interaction and binding strength between the charged groups on the polymers and the encapsulated nucleotides. ,− New cationic polymers (i.e., PBAE (β-amino ester), Charge-altering releasable transporters (CARTs i.e α-amino ester), and PHTA) based on this approach are being investigated to deliver mRNA and short nucleotides for gene editing and vaccines with reduced toxicity and inflammatory response. − However, the in vivo long-term potential toxicity of the degraded products requires careful examination under biologically relevant conditions. The use of PBEA has been employed in the development of mRNA formulations intended for intranasal administration with the assistance of a nebulizer. , This utilization strongly indicates the enhanced stability of nanoparticles in withstanding the process of nebulization.…”

Amino-modified 2-oxazoline copolymers for complexation with DNA

“…Polyplexes are also able to efficiently interact with the cell surface, trigger intracellular uptake and therefore deliver the introduced nucleic acid to its site of action. 2,3 Polymers that may interact electrostatically with the negatively charged phosphate backbone of nucleic acids are mainly those that carry repetitive positive charges in their structure. 4,5 Typically, the amino groups present in these macromolecules are protonated at physiological pH and interact with DNA or RNA.…”

Optimization of precision nanofiber micelleplexes for DNA delivery

“…3,4 Polymeric materials show great promise for addressing this key challenge of NA delivery. [5][6][7] However, new advances are needed if they are to leverage their advantages over other, more popular delivery systems such as lipid nanoparticles and viral vectors. These advantageous characteristics include lower immunogenicity and easier pro-duction, scalability, and versatility.…”

“…These advantageous characteristics include lower immunogenicity and easier pro-duction, scalability, and versatility. 7 Significant challenges also remain for polymeric systems, such as maximizing the cellular transfection efficiency whilst also minimizing unwanted cellular toxicity, 8 as well as addressing issues over their stability, degradation and clearance. 6 Polymeric delivery systems exist in a number of architectures, such as polyplexes, 9 micelleplexes, 10 and bottleplexes.…”